Immunity is mediated by memory cells, which are derived from naive lymphocytes that proliferate and differentiate in response to vaccination or primary infection. Based on evidence from CD8+ T cells, it is currently thought that immune memory comes about because antigenic stimulation causes short-lived naive cells to become stem cell-like, self-renewing memory cells that persist at a stable level for the life of the host. However, during the last funding period we found that: (1) the number of memory CD4+ T cells in the whole body declines after exposure to antigen; (2) the rate of decline for one clonal memory cell population was identical to the rate of decline for that clone in its naive state, and (3) polyclonal naive CD4+ T cells have complex survival characteristics consistent with a mixture of clones with individual half-lives ranging from weeks to years. Based on these findings, we propose to test a new model of immune memory for CD4+ T cells in which individual naive clones vary greatly in their inherent survival times based on their unique TCR and give rise to memory cells with the same survival characteristics as their naive precursor. This model will be tested by measuring the survival times of naive and memory CD4+ T cells from different TCR transgenic clones, determining whether or not polyclonal long-lived naive CD4+ T cells give rise to long-lived memory cells, assessing changes in TCR usage in the naive T cell repertoire over time, determining whether or not naive CD4+ T cells from a TCR transgenic line made one year after immunization are long-lived, assessing the signals required to maintain short and long-lived CD4+ T cell clones, and determining whether or not memory CD4+ T cells undergo self-renewing proliferation. Successful completion of this proposal has the potential to produce a paradigm shift in our understanding of the mechanism of CD4+ T cell memory and suggest new vaccine and immunotherapy strategies.